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  • 1
    In: International Journal of Cancer, Wiley, Vol. 139, No. 12 ( 2016-12-15), p. 2850-2858
    Abstract: What's new? Tumor Treating Fields (TTFields), in which tumor cell division is disrupted by exposure to alternating electric fields, are a promising therapeutic strategy against cancer. In this study, TTFields are shown to enhance the efficacy of paclitaxel in ovarian cancer, both in vitro and in vivo . The feasibility of effectively delivering TTFields across a large nonuniform volume, encompassing ovaries and potential metastatic sites, is demonstrated via electric field measurements in mice and through finite‐element mesh simulations. The results have given impetus to an open‐label pilot investigation of TTFields administered in combination with paclitaxel in patients with recurrent ovarian cancer.
    Type of Medium: Online Resource
    ISSN: 0020-7136 , 1097-0215
    URL: Issue
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    Language: English
    Publisher: Wiley
    Publication Date: 2016
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  • 2
    In: Journal of Visualized Experiments, MyJove Corporation, , No. 123 ( 2017-05-04)
    Type of Medium: Online Resource
    ISSN: 1940-087X
    Language: English
    Publisher: MyJove Corporation
    Publication Date: 2017
    detail.hit.zdb_id: 2259946-0
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  • 3
    In: Neuro-Oncology, Oxford University Press (OUP), Vol. 17, No. suppl 5 ( 2015-11), p. v23.3-v23
    Type of Medium: Online Resource
    ISSN: 1522-8517 , 1523-5866
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2015
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  • 4
    In: Neuro-Oncology, Oxford University Press (OUP), Vol. 20, No. suppl_6 ( 2018-11-05), p. vi30-vi30
    Type of Medium: Online Resource
    ISSN: 1522-8517 , 1523-5866
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2018
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  • 5
    Online Resource
    Online Resource
    American Society of Clinical Oncology (ASCO) ; 2013
    In:  Journal of Clinical Oncology Vol. 31, No. 15_suppl ( 2013-05-20), p. e22138-e22138
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 31, No. 15_suppl ( 2013-05-20), p. e22138-e22138
    Abstract: e22138 Background: TTFields Therapy is an antimitotic treatment modality approved by FDA for the treatment of patients with recurrent glioblastoma (GBM). TTFields act by disruption of spindle microtubule arrangement during metaphase and interference with cytokinesis during anaphase and telophase. These effects are the result of rotation of charged and/or polar macromolecules in the direction of the applied antimitotic fields. We hypothesized that the negatively charged, double stranded DNA fragments induced by ionizing radiation (RT) or ultraviolet light (UV) undergo similar rotation. Double strand break repair relies on proper alignment of the strands during the process of homologous recombination. Thus application of TTFields during the DNA repair process holds the potential of interfering with normal DNA repair. Methods: Cancer cells (786-O renal cell carcinoma) were exposed to TTFields for various durations up to 4 hours after UV or RT treatment. The extent of DNA repair over time was evaluated using the alkaline comet assay (Trevigen, USA). This assay allows the computation of the relative proportion of intact DNA strands and DNA fragments in individual cells after inducing DNA breaks. Results: Exposure of UV treated cells to TTFields for 4 hours led to a significant increase in the content of DNA fragments per cell compared to the content without TTFields exposure (45 + 14%; p=0.012). This increase was accompanied by a significant decrease in the intact DNA content per cell compared to the content of cells not exposed to TTFields (47 + 14%; p=0.005). Inhibition of DNA repair was apparent 1-4 hours after irradiation depending on the extent of DNA damage. Similar results were seen after exposure of the cultures to 2Gy RT (17% increase in DNA fragment content and 14% decrease in intact DNA content at 4 hours). Interestingly, while TTFields did not lead to any DNA damage when applied alone, the application of TTFields for one hour after UV exposure led to a 27 + 29% (p=0.02) increase in the extent of the DNA damage (fragment content). Conclusions: This is the first demonstration that, in addition to its known anti-mitotic effect, TTFields Therapy also inhibits DNA repair and may thus lead to an increase in the cytotoxic effects of therapeutic irradiation.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
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    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2013
    detail.hit.zdb_id: 2005181-5
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  • 6
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 37, No. 15_suppl ( 2019-05-20), p. e20069-e20069
    Abstract: e20069 Background: Malignant pleural mesothelioma (MPM) is an aggressive thoracic cancer mostly linked to asbestos exposure. The standard of care (SOC) therapy for unresectable MPM is cisplatin plus pemetrexed. Treating Fields (TTFields) therapy is an effective anti-neoplastic treatment modality delivered via noninvasive application of low intensity, intermediate frequency, alternating electric fields. We explored the potential use of TTFields alone and in combination with SOC as a treatment for MPM. Methods: NCI-H2052 and MSTO-211H cells were treated at various TTFields frequencies for 72 hours using the inovitro system. The combined treatment of TTFields and cisplatin or pemetrexed was tested by applying TTFields at the optimal frequency together with various drug concentrations. Cell counts, clonogenic potential and induction of apoptosis were determined. TTFields (1.2 V/cm) were applied for 8 days to rats injected to the intrapleural cavity with IL-45 cells, and overall survival was tested. Results: TTFields optimal frequency was 150 kHz for both human cell lines. TTFields application (1.1 V/cm, 72 hours) at 150 kHz led to 45%-51% reduction in cell counts and 46-64%% additional reduction in clonogenic potential. The combined treatment of TTFields and cisplatin or pemetrexed led to a significant reduction in cell count, induction of apoptosis and reduced clonogenic potential as compared to each modality alone (p 〈 0.0001(. TTFields significantly prolonged the survival of rats compared to control group. Safety studies did not reveal any adverse events associated with 150 kHz TTFields application to the rat torso. Conclusions: These results demonstrate that TTFields can be an effective treatment against mesothelioma and the combination with cisplatin or pemetrexed may further enhance treatment efficacy. These results are in consistency with the recent phase 2 study (EF-23 trial) that showed improved overall survival for combined treatment as compared to historical control with no increase in systemic toxicity.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
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    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2019
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  • 7
    In: Pancreatology, Elsevier BV, Vol. 14, No. 1 ( 2014-01), p. 54-63
    Type of Medium: Online Resource
    ISSN: 1424-3903
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2014
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  • 8
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 79, No. 13_Supplement ( 2019-07-01), p. 303-303
    Abstract: Background: Gastric cancer is the fourth most common cancer and the second most common cause of cancer death worldwide. Despite systemic therapies improvement in recent era, long-term survival rates for patients with advanced gastric cancer remains poor. FOLFOX (Oxaliplatin, 5-FU and Leucovorin) is an approved chemotherapy regimen for treatment of gastric cancer. Tumor Treating Fields (TTFields) therapy is an effective anti-neoplastic treatment modality delivered via noninvasive application of low intensity, intermediate frequency, alternating electric fields. The aim of this work is to explore the potential of the use of TTFields alone and in combination with FOLFOX as a treatment for gastric carcinomas. Methods: AGS and KATO III cells were treated for 72 hours with TTFields (1.1 and 1.7 V/cm, respectively) at various frequencies, using the inovitro system. Efficacy of the combined treatment of TTFields and FOLFOX was tested by applying TTFields at the optimal frequency together with various drug concentrations. Cell counts, induction of apoptosis, clonogenic potential and overall effect were determined at the end of treatment. Results: The optimal TTFields frequency leading to the highest reduction in cell counts was found to be 150 kHz for both cell lines resulting in 55% and 52% reduction in cell counts for AGS and KATO III, respectively. In addition, clonogenic potential of both cell lines was reduced by more than 70%. The combined treatment of TTFields with each chemotherapy (Oxaliplatin, 5-FU or Leucovorin), led to a significant reduction in the survival of AGS and KATO III cells (2-way ANOVA, p & lt;0.001 for both cell lines) as compared to each treatment alone. The combined treatment of TTFields with FOLFOX led to further reduction in the overall effect (cytotoxic and clonogenic) of AGS (79%) compared to TTFields alone (65%) and FOLFOX alone (34%). Similar results were observed for the combined treatment of TTFields and FOLFOX in KATO III cells. Conclusions: The results presented in this work demonstrate that TTFields can be an effective treatment against gastric carcinoma and that the combination with FOLFOX may further enhance treatment efficacy. Based on the above, there is a strong rational to continue exploring the potential of the use of TTFields together with standard of care for the treatment of gastric cancer in the clinical settings. Citation Format: Tali Voloshin, Einav Zeevi, Karnit Gotlib, Rosa S. Schneiderman, Mijal Munster, Yaara Porat, Shiri Davidi, Anna Shteingauz, Noa Kaynan, Moshe Giladi, Eilon D. Kirson, Uri Weinberg, Adrian Kinzel, Yoram Palti. The efficacy of the combined treatment of 150 kHz Tumor Treating Fields (TTFields) and FOLFOX in gastric cancer in vitro [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 303.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2019
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    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 9
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 78, No. 13_Supplement ( 2018-07-01), p. 2273-2273
    Abstract: Objective: Tumor Treating Fields (TTFields) therapy is an approved modality for the treatment of glioblastoma. These alternating electric fields were shown to exert an inhibitory effect in numerous cancer cell lines with some variability in the responses of different cell lines. The goal of the present study is to compare characteristics of cell lines based on their response pattern to TTFields. Methods: Forty different human cancerous cell lines were treated for 72 hours with TTFields at respective cell-specific optimal frequency with the same nominal intensity (1.7 V/cm). Cell survival and clonogenicity were determined. Functional analysis of differentially expressed genes and mutations associated with response to TTFields was performed based on the Cancer Cell Line Encyclopedia (CCLE) database. Sensitivity to TTFields was compared with pharmacologic profiling (CCLE). Results: TTFields application demonstrated varying degrees of cytotoxic effects in all cell lines tested. The inhibitory response to TTFields was found to be distributed around an average of 50% with cytotoxic effects ranging between 14% and 86% reductions in cell counts, and a clonogenic effect ranging between no effect and 88% reduction in the number of colonies. In line with TTFields' anti-mitotic properties, a correlation between treatment efficacy and cell doubling time was demonstrated. However, few cell lines demonstrated enhanced treatment efficacy despite long doubling time, suggesting other factors may also be involved in the response to treatment. Pharmacologic profiling based on IC50 values revealed increased sensitivity to lapatinib, PHA-665752 and PLX-4720 within the group of cell lines that were less sensitive to TTFields. Functional analyses of cell line gene expression and mutation data revealed enriched pathways related to DNA damage repair response such as the BRCA1 repair pathway, which validate previous data obtained using different methodologies. Other pathways that were found to be associated with sensitivity to TTFields include cell migration, hypoxia signaling, and oxidative stress. Conclusion: This multiparameter, large-scale comparison of cancer cell line responses demonstrates the broad effectiveness of TTFields in various cell lines and defines the optimal frequency to be applied for each cell line. The data presented in this work suggest that beside anti-mitotic properties, TTFields may have effects on other cellular pathways. The pharmacologic profiling may offer a rational for combining specific agents with TTFields in cells that are less sensitive to the electric fields. Citation Format: Gitit Lavy Shahaf, Moshe Giladi, Rosa S. Schneiderman, Noa Urman, Karnit Gotlieb, Einav Zeevi, Yaara Porat, Mijal Munster, Adrian Kinzel, Uri Weinberg, Eilon D. Kirson, Yoram Palti. Meta-analysis of cancer cell lines based on responses to Tumor Treating Fields (TTFields) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2273.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2018
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    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 10
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 73, No. 8_Supplement ( 2013-04-15), p. 5569-5569
    Abstract: Tumor Treating Fields (TTFields) therapy is an established anti-mitotic treatment modality. The Novo TTF-100A system, which delivers TTFields to the brain received FDA approval for the treatment of patients with Recurrent Glioblastoma (GBM) Brain Tumors. The goal of the present study is to test whether TTFields therapy is effective as a treatment in pre-clinical models of pancreatic and ovarian cancer. TTFields of various frequencies were applied for 72h to cancerous tumor cells using two pairs of perpendicular insulated electrodes. Pancreatic adenocarcinoma and ovarian carcinoma culture growth was significantly reduced compared to controls (65%+10% and 21%+13%, respectively) with a maximal inhibitory effect seen at 150 and 200 kHz (respectively). The surviving cells exhibited increased cell volume (35%+11% and 61%+43% for pancreatic and ovarian cell lines, respectively) and a reduced viability. Fluorescence microscopy and FACS analysis revealed abnormal mitotic figure in the treated cells cultures and an increase in the 4N population, suggesting these cells failed to complete mitosis. Yet, the increase in the 4N cells fraction was too small to explain for the observed increase in cell volume in the entire remaining cell population. Combining TTFields with gemcitabine and paclitaxel commonly used for the treatment of pancreatic and ovarian cancer, enhanced treatment efficacy and led to a further increase in cell volume. The efficacy of TTFields either alone or in combination with 5FU or gemcitabine was tested in hamsters bearing syngeneic, orthotopic pancreatic tumors. In vivo imaging as well as post mortem analysis demonstrated a significant decrease in tumor weight and volume. Compared to chemotherapy treatment alone, TTF had a sensitizing effect and increased tumor response to chemotherapy. Based on previous reports, the observed increase in cell volume is expected to shift the peak response to TTFields to a lower frequency, allowing some of the cells to escape the effect of TTFields. While this is the first proposed mechanism of resistance to TTFields it also opens the possibility of overcoming that resistance using serial application of several frequencies. Citation Format: Moshe Giladi, Rosa S. Schneiderman, Yaara Porat, Mijal Munster, Aviran Itzhaki, Daniel Mordechovich, Shay Cahal, Uri Weinberg, Eilon D. Kirson, Yoram Palti. Tumor Treating Fields inhibit the growth of pancreatic and ovarian cancer in preclinical models . [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5569. doi:10.1158/1538-7445.AM2013-5569
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2013
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    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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